Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary (CHO) cells stably expressing a rat vascular angiotensin II type LA receptor (CHO-AT(1A)). Cyclin D1 prot...
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Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary (CHO) cells stably expressing a rat vascular angiotensin II type LA receptor (CHO-AT(1A)). Cyclin D1 protein expression is regulated by mitogens, and its assembly with the cyclin-dependent kinases induces phosphorylation of the retinoblastoma protein pRb, a critical step in G(1) to S phase cell cycle progression contributing to the proliferative responses. In the present study, we found that in CHO-AT(1A) cells, Ang II induced a rapid and reversible tyrosine phosphorylation of various intracellular proteins including the protein-tyrosine phosphatase SHP-2. Ang II also induced cyclin D1 protein expression in a phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)-dependent manner. Using a pharmacological and a co-transfection approach, we found that p21(ras), Raf-1, phosphatidylinositol 3-kinase and also the catalytic activity of SHP-2 and its Src homology 2 domains are required for cyclin D1 promoter/reporter gene activation by Ang II through the regulation of MAPK/ERK activity. Our findings suggest for the first time that SHP-2 could play an important role in the regulation of a gene involved in the control of cell cycle progression resulting from stimulation of a G protein-coupled receptor independently of epidermal growth factor receptor transactivation.
Angiotensin II (ANG II) increases arterial pressure in fetal sheep and may modulate cardiovascular adaptation before and after birth. The type 1 angiotensin II receptor (AT(1)R) predominates in adult vascular smooth m...
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Angiotensin II (ANG II) increases arterial pressure in fetal sheep and may modulate cardiovascular adaptation before and after birth. The type 1 angiotensin II receptor (AT(1)R) predominates in adult vascular smooth muscle (VSM) and mediates vasoconstriction. In contrast, AT(2)R predominate in fetal tissues and are not known to mediate contraction. Although sheep are commonly used to study cardiovascular development, the ontogeny and distribution of VSM ATR subtypes is unknown. We examined ATR binding characteristics and subtype expression across the umbilicoplacental vasculature and in aorta, carotid, and mesenteric arteries from fetal (n = 44;126-145 d gestation) and postnatal (n = 65;1-120 d from birth) sheep using plasma membranes from tunica media and tissue autoradiography. Binding density (B-max) was similar throughout the umbilicoplacental vasculature (p = 0.5), but only external umbilical arteries and veins and primary placental arteries expressed AT(1)R, whereas subsequent placental branches and fetal placentomes expressed only AT(2)R. Systemic VSM B-max and binding affinity did not change significantly during development (p > 0.1). Fetal systemic VSM, however, expressed only AT(2)R, and binding was insensitive to GTP(gamma)S. Transition to AT(1)R in systemic VSM began 2 wk postnatal and was completed by 3 mo. Before birth, umbilical cord vessels are the primary site of AT(1)R expression in fetal sheep, and AT(2)R seem to predominate in systemic VSM until 2-4 wk postnatal.
Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cells (VSMC) via its specific receptor AT1 subtype, possibly leading to atherosclerosis in hypertension. On the other hand, a cytokine interferon...
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Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cells (VSMC) via its specific receptor AT1 subtype, possibly leading to atherosclerosis in hypertension. On the other hand, a cytokine interferon (IFN)-gamma has been shown to have an anti-atherosclerotic effect. In the present study, we examined a possible role of IFN-gamma in AT1 receptor gene regulation in VSMC. A firefly luciferase expression vector driven by the rat AT1a receptor gene promoter (similar to 3.2 kb) was transfected into the cultured rat VSMC, and luciferase expression was determined to estimate the transcription function of the AT1a receptor gene promoter. RT-PCR was also carried out to determine mRNA expression of AT1a receptor in VSMC. IFN-gamma treatment decreased AT1a receptor mRNA expression as well as luciferase expression in a dose-dependent manner. The analysis with deletion DNA fragments showed that the IFN-responsive element was located between -987 and -331 positions, where multiple GAS (gamma interferon activated site)-like elements were identified. The expression suppression was reversed by either a MAPKK inhibitor PD98059 or a Jak-2 inhibitor AG-490. These results suggest that IFN-gamma can inhibit AT1 receptor expression at gene transcription level, and that the transcription suppression is dependent on MAP kinase and Jak-2. Inhibition of AT1a receptor expression may possibly be implicated in the anti-atherosclerotic action of IFN-gamma in VSMC. (C) 1999 Academic Press.
High sodium intake causes cardiac hypertrophy independently of increases in blood pressure. Aldosterone is synthesized in extraadrenal tissues such as blood vessels, brain, and heart. Effects of 8 weeks of high sodium...
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High sodium intake causes cardiac hypertrophy independently of increases in blood pressure. Aldosterone is synthesized in extraadrenal tissues such as blood vessels, brain, and heart. Effects of 8 weeks of high sodium intake on cardiac aldosterone synthesis, as well as cardiac structure, mass, and aldosterone production, levels of mRNA coding for aldosterone synthase (CYP11B2) and the angiotensin TI AT 1 receptor, were studied in normotensive Wistar-Kyoto (WKY) rats. Isolated rat hearts were perfused for 2 hr, and the perfusate was analyzed by high-performance liquid chromatography and mass spectrometry. Aldosterone synthase activity was estimated from the conversion of [C-14]deoxycorticosterone to [C-14]aldosterone. Levels of mRNA for CYP11BZ and AT 1 receptor were determined by competitive polymerase chain reactions. A high sodium intake for 8 weeks produced left ventricular hypertrophy without elevation of blood pressure. Plasma aldosterone concentrations and plasma renin concentrations were decreased by high sodium intake. Aldosterone production, activity of aldosterone synthase, and expression of mRNA for CYP11B2 and AT 1 receptor were increased in hearts of rats with high sodium intake. These results suggest that high sodium intake increases cardiac aldosterone synthesis, which may contribute to cardiac hypertrophy independently of the circulating renin-angiotensin-aldosterone system.
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